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Updated: Sep 11, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Optimal control of multiple myeloma assuming drug resistance and off-target effects
James G Lefevre1,2, Brodie A J Lawson2,3, Pamela M Burrage2,3
1School of Mathematics and Physics, The University of Queensland, Brisbane, Queensland, Australia.
Abstract:
Multiple myeloma (MM) is a plasma cell cancer that occurs in the bone marrow. A leading treatment for MM is the monoclonal antibody Daratumumab, targeting the CD38 receptor, which is highly overexpressed in myeloma cells. In this work we model drug resistance via loss of CD38 expression, which is a proposed mechanism of resistance to Daratumumab treatment. We develop an ODE model that includes drug resistance via two mechanisms: a direct effect in which CD38 expression is lost without cell death in response to Daratumumab, and an indirect effect in which CD38 expression switches on and off in the cancer cells; myeloma cells that do not express CD38 have lower fitness but are shielded from the drug action. The model also incorporates competition with healthy cells, death of healthy cells due to off-target drug effects, and a Michaelis-Menten type immune response. Using optimal control theory, we study the effect of the drug resistance mechanisms and the off-target drug effect on the optimal treatment regime. We identify a general increase in the duration and costs of optimal treatment, as a result of these added mechanisms. Several distinct optimal treatment regimes are identified within the parameter space.
Insights
Drug resistance in multiple myeloma (MM) can occur through loss of CD38 expression, a target for Daratumumab. Our model shows this resistance increases treatment duration and cost, revealing distinct optimal treatment strategies.
Area of Science:
- Oncology
- Mathematical Biology
- Pharmacology
Background:
- Multiple myeloma (MM) is a bone marrow cancer.
- Daratumumab, a CD38-targeting antibody, is a key MM treatment.
- CD38 downregulation is a proposed resistance mechanism to Daratumumab.
Purpose of the Study:
- To model drug resistance in MM via CD38 loss.
- To investigate the impact of resistance mechanisms on optimal treatment strategies.
- To analyze off-target effects and immune response in treatment optimization.
Main Methods:
- Developed an ordinary differential equation (ODE) model.
- Incorporated direct and indirect CD38 loss mechanisms.
- Applied optimal control theory to determine treatment regimes.
Main Results:
- Drug resistance mechanisms generally increase optimal treatment duration and cost.
- Off-target drug effects and immune response influence treatment strategies.
- Identified several distinct optimal treatment regimes within the model's parameter space.
Conclusions:
- CD38 downregulation significantly impacts Daratumumab treatment efficacy in MM.
- Mathematical modeling is crucial for understanding complex resistance dynamics.
- Optimized treatment strategies are necessary to overcome drug resistance and improve patient outcomes.
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